Obsessive-compulsive disorder (OCD) affects 1-2% of children and adolescents, causing significant distress and impairments from the unrelenting obsessional thoughts and compulsive behaviors. In some cases, childhood-onset OCD appears to arise as a consequence of common childhood infections, including Group A beta-hemolytic streptococcal (GABHS) infections (strep throat and Scarlet fever). Children whose symptoms begin or exacerbate following GABHS infections may belong to a subgroup of neuropsychiatric disorders identified by the acronym PANDAS (for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections). The PANDAS subgroup shares several common clinical characteristics and may share a common pathophysiology for their symptoms. The postulated etiology for the PANDAS subgroup is that specific strains of Group A streptococci, in genetically susceptible individuals, elicit the production of cross-reactive antibodies which recognize antigens not only on the GABHS cell wall, but also in the host brain tissue, eliciting obsessions, compulsions, tics and other neuropsychiatric symptoms. The cross-reactive antibodies have been shown to correlate with other anti-streptococcal antibodies and also with neuropsychiatric symptom severity, with highest titers seen in children acutely ill with Sydenham chorea or PANDAS symptomatology. A recent report by Yaddanapudi et al (Mol Psychiatry advance on-line publication, 11 Aug 2009; doi10.1038/mp.2009.77)demonstrated that passive transfer of these cross-reactive antibodies resulted in stereotypies and other neurologic symptoms in the recipient mice. This paper adds to data from more than 15 years of research at the NIMH intramural program and elsewhere, demonstrating that: the PANDAS subgroup has a specific and identifiable symptom course (marked most notably by the acute, abrupt, overnight onset of symptoms (zero to sixty in less than 24 hours); the cross-reactive antibodies correlate with both GABHS infection status and neuropsychiatric symptom severity; prevention of GABHS infections through antibiotic prophylaxis results in prevention of neuropsychiatric symptom exacerbations; and, treatment of acutely ill children with immunomodulatory therapies specifically, intravenous immunoglobulin (IVIG) or plasmapheresis results in dramatic reductions in symptom severity. This line of research is unusual, in that it reversed the typical bench to bedside progression and took clinical observations and experiences into the laboratory in search of information about etiopathogenic mechanisms. The results proved exciting, as the cross-reactive antibodies identified antigenic targets in the CNS which might provide new targets for therapeutic interventions. The PANDAS research represents a collaborative relationship among this branch (Dr. Swedo) and Dr. James Leckman and colleagues at the Yale University Child Study Center and Dr. Madeleine Cunningham of the University of Oklahoma Health Sciences Center. Drs. Swedo, Leckman, and Cunningham were the joint recipients of an NIH Bench to Bedside award which is helping to fund a multi-site placebo-controlled trial of intravenous immunoglobulin (IVIG) for severely ill children with PANDAS.(NCT 01281969) Up to 50 children (3-12 yrs old) will be enrolled in the trial and randomly assigned to receive an infusion of IVIG or placebo. Primary outcome variables are change in severity of obsessive-compulsive symptoms (rated with the Y-BOCS) and overall symptom severity (CGI-severity and CGI-change scales) at six weeks following blinded infusion of study drug. Additional clinical variables of interest include the change in PANDAS-specific symptoms (rated with the PANS scale) and relationship of response to IVIG therapy to changes in CSF and serum markers of disease status. In addition to the information provided about the utility of IVIG treatment for PANDAS, the trial will generate biological samples to be analyzed by Dr. Cunningham and others, with the goal of further delineating the pathologic role of the cross-reactive antibodies, as well as potentially developing biomarkers for disease activity and treatment response. More information about the study is available at: http://clinicaltrials.gov/ct2/show/NCT01281969?term=bethesda%2C+MD+%2B+PANDAS&rank=1.